The preparation and certain uses of 4-((9-((3S)-tetrahydro-3-furanyl)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-2-yl)amino)-trans-cyclohexanol, alternatively referred to as (1S,4r)-4-(9-((S)-tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino)cyclohexanol and 4-(9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-ylamino)-cyclohexan-1-ol, have been described in U.S. Pat. Nos. 7,521,446, 7,723,340, and 7,759,342; U.S. Pat. App. Pub. Nos. 2009/275564, 2009/312320, 2010/249066, and 2009/0048275; and International Pub. Nos. WO 2006/076595, WO 2007/127382, and WO 2008/057252; the disclosure of each of which is incorporated herein by reference in its entirety.
The identification and selection of a formulation of a pharmaceutical compound is complex, given that a change in a formulation may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in safety, processing, stability, solubility and bioavailability, among other important pharmaceutical characteristics.
Notably, the various excipients employed in a formulation of a pharmaceutical compound can have a profound effect on the manufacturing process, wherein characteristics such as flowability (e.g., blend flow), hardness, compressibility, sticking, filming and capping can be affected by the identity and amount of the excipients employed.
Potential formulations include, but are not limited to solid, liquid and aerosol formulations. Potential solid formulations include, but are not limited to, tablet and capsule formulations. The variety of possible formulations creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of the optimal formulation is of great importance in the development of a safe, effective, stable and marketable pharmaceutical product.
Notably, 4-((9-((3S)-tetrahydro-3-furanyl)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-2-yl)amino)-trans-cyclohexanol is a fine white powder with a fluffy appearance, which exhibits poor flow. In addition, 4-((9-((3S)-tetrahydro-3-furanyl)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-2-yl)amino)-trans-cyclohexanol exhibits low aqueous solubility, at a level of less than 1 mg/mL.
Accordingly, there is a need in the art for formulations that impart more desirable chemical and physical properties.
Teratogenic agents can disturb the growth of an embryo or fetus. Accordingly, exposure to teratogenic agents should be avoided by females who are pregnant or may become pregnant and by males who may come into contact with such females. One strategy for reducing or minimizing such exposure for teratogenic pharmaceutical agents is to provide the final product in a form that minimizes such exposure, such as a capsule formulation or a coated tablet formulation. Such formulations can reduce the exposure of, for example, workers who might come into contact with the teratogenic agent in a manufacturing setting, as well as patients being administered the teratogenic agent, in addition to health care providers and others who might come into contact with the teratogenic agent.
Accordingly, there is a need in the art for formulations that reduce the risk of exposure to teratogenic pharmaceutical agents.
Capsule formulations, wherein the drug is contained within a capsule shell, offer a route to such formulations. Capsule formulations can comprise a hard outer shell that contains the drug formulation inside, thus reducing exposure to the drug after the manufacturing process is complete. In addition, capsule formulations allow for manufacturing processes that can reduce the handling of the solid formulation. For instance, with the appropriate choice of excipients, it may be possible to direct-fill into capsules, thus reducing exposure to the drug during compression (tablet), film coating and packaging operations. Thus, capsule formulations also may reduce exposure to the drug during the manufacturing process.
Citation or identification of any references in this application is not to be construed as an admission that the references are prior art to the present application.